PB1-Lip@M-CST nanoparticles reduce myocardial infarct size by 48% in mice via CXCR4/PI3K/AKT1 pathway

Reperfusion therapy for severe ischemic heart disease is often limited by myocardial ischaemia-reperfusion injury (MIRI), which exacerbates cardiomyocyte damage through oxidative stress, inflammation, and apoptosis. Current approaches struggle with targeted delivery and mitigating this secondary injury. There's a critical need for strategies that can specifically protect cardiac tissue post-reperfusion. This study addresses this gap by developing a biomimetic nanoparticle designed for enhanced cardiac homing and immune evasion to deliver a cardioprotective agent.

Researchers developed PB1-Lip@M-CST nanoparticles, consisting of procyanidin B1 (PB1)-loaded liposomes coated with macrophage membranes and surface-functionalized with the cardiac-specific targeting peptide CSTSMLKAC (CST). In vitro, they assessed phagocytic uptake by RAW 264.7 macrophages and internalization in HL-1 cardiomyocytes. Cardioprotection was evaluated in CoCl2-induced hypoxia-reoxygenation models. In vivo, a mouse model of MIRI received intravenous administration of PB1-Lip@M-CST to assess systemic circulation, cardiac accumulation, infarct size, left ventricular ejection fraction, serum injury biomarkers, and long-term fibrosis and apoptosis.

In vitro, PB1-Lip@M-CST significantly reduced phagocytic uptake by RAW 264.7 macrophages and enhanced internalization in HL-1 cardiomyocytes in a CST-dependent manner. It provided superior protection in CoCl2-induced hypoxia-reoxygenation by suppressing reactive oxygen species, lipid peroxidation, proinflammatory cytokines, and apoptosis. Mechanistically, these effects were mediated via modulation of the CXCR4-associated PI3K/AKT1 signaling pathway and restoration of the BAX/BCL-2 balance. In a mouse MIRI model, intravenous PB1-Lip@M-CST prolonged systemic circulation and achieved markedly enhanced cardiac accumulation. The therapeutic impact was substantial:

Infarct size was reduced to 25.58 ± 2.96% (compared to 49.22 ± 3.03% in the model group), representing a 48% reduction. Left ventricular ejection fraction was preserved at 50.42 ± 8.74%, serum injury biomarkers were attenuated, and long-term fibrosis and apoptosis were inhibited, all with an excellent biosafety profile.